November 27, 2012
The diagnosis of latent tuberculosis (TB) is important in patients with ESRD as the rate of activation is 50 times that of the general population. Additionally, some dialysis patients will go on to transplantation and need treatment of latent TB prior to immunosuppression. Unfortunately, the standard diagnostic tool, the tuberculin skin test, requires an intact immune system and can give false positives in patients who are vaccinated with BCG. Interferon gamma release assays (IGRAs; QuantiFERON-TB Gold in-Tube (QFT), and T-SPOT.TB) have recently emerged as potential ways to diagnose TB infection in many individuals. What is the use of these tests in ESRD and transplant patients? Corresponding author Dr. Angela Webster (AW) from the Sydney School of Public Health, Australia, discusses this recent systematic review published in AJKD with Dr. Joel Topf (eAJKD), eAJKD Advisory Board member.
eAJKD: Systematic reviews seem to be very intensive, especially when properly done. How did you approach this question?
AW: To reduce bias and person-error, and in line with general methodological guidelines for systematic reviews, we ensured the search review, data abstraction, and bias assessment was done in duplicate by two authors working independently. In order to drag the net as wide as possible in the online medical databases, we used a highly sensitive search strategy that looked for terms associated with testing, kidney disease, and tuberculosis. Most studies, over 812 citations, were excluded based on title and abstract. Needless to say, reference management software is invaluable in this process. In total we found 47 studies, but only 30 contained enough data to contribute to the meta-analysis.
eAJKD: Have you noticed a high rate of TB in your clinical practice?
AW: My clinical experience from Scotland and subsequently in Sydney seemed to suggest that although national rates of TB are low and relatively stable compared to other parts of the world (like Sub-Saharan Africa), cases of TB seemed to be more common in people with ESRD. These cases are often diagnosed as active disease, with more extra-pulmonary disease. Recent work in Australia, by cleverly linking datasets, showed that after adjusting for country of birth, sex, age, and indigenous status, the adjusted relative risk of TB in people on dialysis was almost 8 times that of the general population. Without adjusting, largely because of the over representation of people born overseas and indigenous people, the risk of individuals on dialysis was over 17 times that of the general population (see Dobler et al article).
eAJKD: Have you faced clinical dilemmas stemming from the difficulty of interpreting skin tests? Do you regularly use IGRA?
AW: I believe any person under the care of a renal service diagnosed with active TB should be considered as a serious adverse clinical event, and one that could have been prevented by detection in the latent stage. I think nephrologists often do not evaluate their patient’s TB risk. This may be due to lack of knowledge, but also because the tools we had to work with are flawed. The tuberculin skin test (TST) is hard to deliver and interpret. It has the misfortune of being labor intensive while also requiring a skilled operator to read the results reliably. We know that many ESRD patients are unable to mount an immune response so the TST is subject to false negatives, and prior BCG vaccination can cause false positives.
IGRAs have changed our approach. These tests are easy to perform and the results are reported electronically alongside our other regular test sets. So now, when clinical suspicion of latent TB is moderate or high, I can easily get an IGRA on the spot.
eAJKD: It looks like the major hurdle in studying this clinical question is related to the lack of a reliable gold standard for diagnosis. Discuss how you used clinical criteria to cobble together a diagnosis of latent TB?
AW: When there is no good existing test, establishing whether a new test should replace the old is not simple. Unfortunately, diagnosing latent TB is not the only clinical situation where this conundrum arises. In our review, we assessed how well the test results of ELISA and ELISPOT based IGRAs correlated with individual risk factors for latent tuberculosis. In effect, we are relating the results of these tests with other relevant clinical criteria. The advantage of this method is that we are able to provide some information about the clinical usefulness of a test, and how it compares to other tests. The disadvantage of this method is that we cannot calculate the conventional estimates of diagnostic accuracy, i.e., sensitivity, specificity, or positive and negative predictive values. Of course, we were also limited by the studies that had been done, but at the very least, we have exposed some gaps in knowledge that might help set a research agenda in this area.
eAJKD: Could you briefly discuss the difference between the QFT and TSPOT.TB?
AW: When anti-mycobacterial T cells are challenged with tuberculosis antigen, they respond by releasing the cytokine interferon gamma. The QuantiFERON and TSPOT.TB tests work by artificially inducing this response in T cells harvested in patient blood samples. Both tests measure the interferon gamma response produced by the harvested T cells, but through two slightly different enzyme immunoassay technologies. The QuantiFERON test is an enzyme-linked immunosorbent assay (ELISA), which measures the concentration of interferon gamma in a blood sample after it has been exposed to TB antigen. The TSPOT.TB test is an enzyme-linked immunospot assay (ELISPOT), which measures the number of interferon gamma producing cells in a blood sample.
eAJKD: If you were to design the ideal study without the limitation of using risk factor assessment as the gold standard, what would it look like?
AW: To answer questions about diagnostic accuracy, the best study design would compare the performance of a new test (in this case QuantiFERON and TSPOT.TB) against a gold standard test. Estimates of test accuracy derived from these studies are clinically useful because they quantify how much confidence we can have in the test results. When there is no gold standard and such studies are not possible, one way to evaluate the usefulness of a test is to study its effects on treatment. With no limitations on money, a study of test-directed treatment would be an ideal way of assessing the clinical value of tests for latent TB. This would likely still not be feasible given the numbers of people required to detect a difference and the necessary follow-up.
In the future, a clinical algorithm that takes into account multiple test results and risk factors to derive an absolute risk of latent TB would be useful for clinicians. Perhaps this should be our next project?
eAJKD: You mention that no specific guidelines exist for TB testing in ESRD patients. What would you propose as the recommendation? Would you want both the TST and IGRA, or use a survey of risk factors (x-ray, history of clinical exposure)?
AW: From our work in patients with end-stage kidney disease, the evidence says ELISA-based IGRAs correlate much better with clinical risk factors for latent TB and BCG vaccination status than the TST. Whether this is the same for ELISPOT-based IGRAs is unclear. Although the estimates were similar to those of the ELISA-based IGRAs, the evidence was more sparse, so we are left with uncertainty. Until further evidence becomes available to the contrary, we propose that ELISA-based IGRAs should be the first line test for latent TB investigation in patients with end-stage kidney disease.